The present invention is generally in the area of drug delivery, and is particularly an improved method for transdermal drug delivery.
Transdermal drug delivery (TDD) offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias, In Percutaneous Absorption: Mechanisms-Methodology-Drag Delivery., Bronaugh, R. L., Maibach, H. 1. (Ed), pp 1-12, Marcel Dekker, New York, 1989. The word "transdermal" is used herein as a generic term. However, in actuality, transport of drugs occurs only across the epidermis where the drug gets absorbed in the blood capillaries. When compared to injections, TDD eliminates the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic proteins, because proteins are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, proteins such as interferons are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value, and transdermal devices are easier to use than injections.
In spite of these advantages, very few drugs and no proteins or peptides are currently administered transdermally for clinical applications because of the low skin permeability to drugs. This low permeability is attributed to the stratum corneum (SC), the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G. L., In Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery.; Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, New York, 1989). Several methods, which include chemical enhancers (Burnette, R. R. In Developmental Issues and Research Initiatives; Hadgraft J., G., R. H., Eds., Marcel Dekker: 1989; pp. 247-288) and electricity (Prausnitz Proc. Natl. Acad. Sci. USA 90, 10504-10508 (1993); Walters, K. A., in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Ed. Hadgraft J., Guy, R. H., Marcel Dekker, 1989), have been proposed to enhance transdermal drug transport. However, the efficacy of these methods in enhancing transdermal protein transport has been limited by the large protein size and relatively low electric charge on the proteins.
Ultrasound has been shown to enhance transdermal transport of low-molecular weight drugs (molecular weight less than 500) across human skin, a phenomenon referred to as sonophoresis (Levy, J. Clin Invest. 1989, 83, 2974-2078; Langer, R., In "Topical Drug Bioavailability, Bioequivalence, and Penetration"; pp. 91-103, Shah V. P., M. H. I., Eds. (Plenum: New York, 1993); Frideman, R. M., `Interferons: A Primer`, Academic Press, New York, 1981)). In a recent study of sonophoresis, it has been shown that application of ultrasound at therapeutic frequencies (1 MHz) induces growth and oscillations of air pockets present in the keratinocytes of the SC (a phenomenon known as cavitation). These oscillations disorganize the SC lipid bilayers thereby enhancing transdermal transport. However, application of therapeutic ultrasound does not induce transdermal transport of high-molecular weight proteins.
Transdermal drug delivery offers an advantageous alternative to oral delivery and injections. However, its applications are restricted to only a few drugs because of the extremely low skin permeability to drugs. A variety of approaches have been suggested to enhance transdermal transport of drugs. These include: i) use of chemicals to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation Enhancement"; Hsieh, D. S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994); ii) applications of electric fields to create transient transport pathways [electroporation] or to increase the mobility of charged drugs through the skin [iontophoresis], and iii) application of ultrasound [sonophoresis].
Sonophoresis has been shown to enhance transdermal transport of various drugs. Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to the therapeutic ultrasound (frequency in the range of 1 MHz-3 MHz, and intensity in the range of 0-2 W/cm.sup.2) (Kost, In Topical Drug Bioavailability Bioequivalence and Penetration, pp. 91-103, Maibach, H. I., Shah, V. P. (Ed) Plenum Press, New York, 1993; U.S. Pat. No. 4,767,402 to Kost, et al.). It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. In many cases, no enhancement of transdermal drug transport has been observed upon ultrasound application. Accordingly, a better selection of ultrasound parameters is needed to induce a higher enhancement of transdermal drug transport by sonophoresis.
It is therefore an object of the present invention to provide an improved method for transdermal drug delivery.
It is a further object of the present invention to provide conditions for using sonophoresis for transdermal drug delivery.